Nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) are being increasingly recognized as a cause of chronic liver disease in the USA. NASH is thought to represent a serious form of fatty liver disease, characterized by hepatic steatosis associated with evidence of necroinflammatory changes such as ballooning degeneration of hepatocytes, Mallory?s hyaline and variable degrees of fibrosis. The histopathologic features of NASH resemble those of alcoholic liver disease, but are found in the absence of significant alcohol intake. The most common risk factors associated with NASH are type II diabetes mellitus, obesity, use of certain medications, and hyper-triglyceridemia. It has been estimated that up to 20% of the population may have fatty liver, and up to 3% may have NASH. NASH may have a high rate of progression to cirrhosis; furthermore, it is likely that NASH is the cause in a significant proportion of patients undergoing liver transplantation for "cryptogenic" liver disease. Therefore, the morbidity, mortality and direct and indirect health care costs associated with NASH are likely to be substantial. However, our understanding of the clinical features, pathogenesis and natural history of NASH is limited by the absence of large epidemiologic studies, and the lack of standardized diagnostic and histopathologic criteria for the diagnosis of this disorder. Recent data suggest that a common feature among patients with nonalcoholic fatty liver disease is insulin resistance, which may be primary or secondary, leading to hepatic accumulation of free fatty acids and steatosis. It has been postulated that steatosis may represent the "first hit" and that one or more "second hits" such as iron overload, mitochondrial dysfunction, activity of cytochrome P450 2E1, 4A1 or other factors may lead to progressive hepatocellular injury and fibrosis (NASH). There are no proven therapies for NASH. Although correction of underlying metabolic defects, low-fat diet, ursodeoxycholic acid therapy and weight loss have been suggested, it is unclear whether any of these treatments are effective. Establishment of the NASH clinical trials network will be an excellent opportunity to establish standardized criteria for diagnosis of this disease, study the natural history and progression of the disease in a large cohort of patients and rapidly evaluate novel treatments. The PI has a long and successful track record of collaborative research in multicenter NIH clinical trials. He has also accumulated a unique cohort of over 100 patients with biopsy proven NASH representing diverse ethnic backgrounds in a major geographic region of the country. The PI also has access to a large pediatric population with NASH. He currently has an ongoing established research program on the pathogenesis and treatment of NASH. He has proposed two studies for the NASH Clinical Research Network that will advance our understanding of this disease.